Cadmium (CASRN 7440-43-9)

Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data, as outlined in the IRIS assessment development process. Sections I (Health Hazard Assessments for Noncarcinogenic Effects) and II (Carcinogenicity Assessment for Lifetime Exposure) present the conclusions that were reached during the assessment development process. Supporting information and explanations of the methods used to derive the values given in IRIS are provided in the guidance documents located on the IRIS website.

STATUS OF DATA FOR Cadmium

File First On-Line 03/31/1987

Category (section)

Status

Last Revised

Oral RfD Assessment (I.A.)

on-line

02/01/1994

Inhalation RfC Assessment (I.B.)

no data

Carcinogenicity Assessment (II.)

on-line

06/01/1992

_I.
Chronic Health Hazard Assessments for Noncarcinogenic Effects

_I.A.
Reference Dose for Chronic Oral Exposure (RfD)

Substance Name — Cadmium
CASRN — 7440-43-9
Last Revised — 02/01/1994

The oral Reference Dose (RfD) is based on the assumption that thresholds
exist for certain toxic effects such as cellular necrosis. It is expressed
in units of mg/kg-day. In general, the RfD is an estimate (with uncertainty
spanning perhaps an order of magnitude) of a daily exposure to the human
population (including sensitive subgroups) that is likely to be without
an appreciable risk of deleterious effects during a lifetime. Please refer
to the Background Document for an elaboration of these concepts. RfDs
can also be derived for the noncarcinogenic health effects of substances
that are also carcinogens. Therefore, it is essential to refer to other
sources of information concerning the carcinogenicity of this substance.
If the U.S. EPA has evaluated this substance for potential human carcinogenicity,
a summary of that evaluation will be contained in Section II of this file.

__I.A.1.
Oral RfD Summary

Critical Effect

Experimental Doses*

UF

MF

RfD

Significant
proteinuria

Human studies
involving chronic
exposures

U.S. EPA, 1985

NOAEL (water): 0.005
mg/kg/day

NOAEL (food): 0.01
mg/kg/day

10

10

1

1

5E-4 mg/kg/day
(water)

1E-3 mg/kg/day
(food)

* Conversion Factors: See text for discussion

__I.A.2. Principal and Supporting Studies (Oral RfD)

A concentration of 200 ug cadmium (Cd)/gm wet human renal
cortex is the highest renal level not associated with significant proteinuria
(U.S. EPA, 1985). A toxicokinetic model is available to determine the
level of chronic human oral exposure (NOAEL) which results in 200 ug Cd/gm
wet human renal cortex; the model assumes that 0.01% day of the Cd body
burden is eliminated per day (U.S. EPA, 1985). Assuming 2.5% absorption
of Cd from food or 5% from water, the toxicokinetic model predicts that
the NOAEL for chronic Cd exposure is 0.005 and 0.01 mg Cd/kg/day from
water and food, respectively (i.e., levels which would result in 200 ug
Cd/gm wet weight human renal cortex). Thus, based on an estimated NOAEL
of 0.005 mg Cd/kg/day for Cd in drinking water and ian UF of 10, an RfD
of 0.0005 mg Cd/kg/day (water) was calculated; an equivalent RfD for Cd
in food is 0.001 mg Cd/kg/day (see Section VI.A. for references).

__I.A.3.
Uncertainty and Modifying Factors (Oral RfD)

UF — This uncertainty factor is used to account for intrahuman
variability to the toxicity of this chemical in the absence of specific
data on sensitive individuals.

MF — None

__I.A.4.
Additional Studies/Comments (Oral RfD)

Cd is unusual in relation to most, if not all, of the
substances for which an oral RfD has been determined in that a vast quantity
of both human and animal toxicity data are available. The RfD is based
on the highest level of Cd in the human renal cortex (i.e., the critical
level) not associated with significant proteinuria (i.e., the critical
effect). A toxicokinetic model has been used to determine the highest
level of exposure associated with the lack of a critical effect. Since
the fraction of ingested Cd that is absorbed appears to vary with the
source (e.g., food vs. drinking water), it is necessary to allow for this
difference in absorption when using the toxicokinetic model to determine
an RfD.

__I.A.5.
Confidence in the Oral RfD

Study — Not applicable
Database — High
RfD — High

The choice of NOAEL does not reflect the information from
any single study. Rather, it reflects the data obtained from many studies
on the toxicity of cadmium in both humans and animals. These data also
permit calculation of pharmacokinetic parameters of cadmium absorption,
distribution, metabolism and elimination. All of this information considered
together gives high confidence in the database. High confidence in either
RfD follows as well.

_I.B.
Reference Concentration for Chronic Inhalation Exposure (RfC)

_II.
Carcinogenicity Assessment for Lifetime Exposure

Substance Name — Cadmium
CASRN — 7440-43-9
Last Revised — 06/01/1992

Section II provides information on three aspects of the
carcinogenic assessment for the substance in question; the weight-of-evidence
judgment of the likelihood that the substance is a human carcinogen, and
quantitative estimates of risk from oral exposure and from inhalation
exposure. The quantitative risk estimates are presented in three ways.
The slope factor is the result of application of a low-dose extrapolation
procedure and is presented as the risk per (mg/kg)/day. The unit risk
is the quantitative estimate in terms of either risk per ug/L drinking
water or risk per ug/cu.m air breathed. The third form in which risk is
presented is a drinking water or air concentration providing cancer risks
of 1 in 10,000, 1 in 100,000 or 1 in 1,000,000. The rationale and methods
used to develop the carcinogenicity information in IRIS are described
in The Risk Assessment Guidelines of 1986 (EPA/600/8-87/045) and in the
IRIS Background Document. IRIS summaries developed since the publication
of EPA's more recent Proposed Guidelines for Carcinogen Risk Assessment
also utilize those Guidelines where indicated (Federal Register 61(79):17960-18011,
April 23, 1996). Users are referred to Section I of this IRIS file for
information on long-term toxic effects other than carcinogenicity.

_II.A.
Evidence for Human Carcinogenicity

__II.A.1.
Weight-of-Evidence Characterization

Classification — B1; probable human carcinogen

Basis — Limited evidence from occupational epidemiologic
studies of cadmium is consistent across investigators and study populations.
There is sufficient evidence of carcinogenicity in rats and mice by inhalation
and intramuscular and subcutaneous injection. Seven studies in rats and
mice wherein cadmium salts (acetate, sulfate, chloride) were administered
orally have shown no evidence of carcinogenic response.

__II.A.2.
Human Carcinogenicity Data

Limited. A 2-fold excess risk of lung cancer was observed
in cadmium smelter workers. The cohort consisted of 602 white males who
had been employed in production work a minimum of 6 months during the
years 1940-1969. The population was followed to the end of 1978. Urine
cadmium data available for 261 workers employed after 1960 suggested a
highly exposed population. The authors were able to ascertain that the
increased lung cancer risk was probably not due to the presence of arsenic
or to smoking (Thun et al., 1985). An evaluation by the Carcinogen Assessment
Group of these possible confounding factors has indicated that the assumptions
and methods used in accounting for them appear to be valid. As the SMRs
observed were low and there is a lack of clear cut evidence of a causal
relationship of the cadmium exposure only, this study is considered to
supply limited evidence of human carcinogenicity.

An excess lung cancer risk was also observed in three
other studies which were, however, compromised by the presence of other
carcinogens (arsenic, smoking) in the exposure or by a small population
(Varner, 1983; Sorahan and Waterhouse, 1983; Armstrong and Kazantzis,
1983).

Four studies of workers exposed to cadmium dust or fumes
provided evidence of a statistically significant positive association
with prostate cancer (Kipling and Waterhouse, 1967; Lemen et al., 1976;
Holden, 1980; Sorahan and Waterhouse, 1983), but the total number of cases
was small in each study. The Thun et al. (1985) study is an update of
an earlier study (Lemen et al., 1976) and does not show excess prostate
cancer risk in these workers. Studies of human ingestion of cadmium are
inadequate to assess carcinogenicity.

__II.A.3.
Animal Carcinogenicity Data

Exposure of Wistar rats by inhalation to cadmium as cadmium
chloride at concentrations of 12.5, 25 and 50 ug/cu.m for 18 months, with
an additional 13-month observation period, resulted in significant increases
in lung tumors (Takenaka et al., 1983). Intratracheal instillation of
cadmium oxide did not produce lung tumors in Fischer 344 rats but rather
mammary tumors in males and tumors at multiple sites in males (Sanders
and Mahaffey, 1984). Injection site tumors and distant site tumors (for
example, testicular) have been reported by a number of authors as a consequence
of intramuscular or subcutaneous administration of cadmium metal and chloride,
sulfate, oxide and sulfide compounds of cadmium to rats and mice (U.S.
EPA, 1985). Seven studies in rats and mice where cadmium salts (acetate,
sulfate, chloride) were administered orally have shown no evidence of
a carcinogenic response.

__II.A.4.
Supporting Data for Carcinogenicity

Results of mutagenicity tests in bacteria and yeast have
been inconclusive. Positive responses have been obtained in mutation assays
in Chinese hamster cells (Dom and V79 lines) and in mouse lymphoma cells
(Casto, 1976; Ochi and Ohsawa, 1983; 0berly et al., 1982).

Conflicting results have been obtained in assays of chromosomal
aberrations in human lymphocytes treated in vitro or obtained from exposed
workers. Cadmium treatment in vivo or in vitro appears to interfere with
spindle formation and to result in aneuploidy in germ cells of mice and
hamsters (Shimada et al., 1976; Watanabe et al., 1979; Gilliavod and Leonard,
1975).

The data were derived from a relatively large cohort.
Effects of arsenic and smoking were accounted for in the quantitative
analysis for cadmium effects.

An inhalation unit risk for cadmium based on the Takenaka
et al. (1983) analysis is 9.2E-2 per (ug/cu.m). While this estimate is
higher than that derived from human data [1.8E-3 per (ug/cu.m)] and thus
more conservative, it was felt that the use of available human data was
more reliable because of species variations in response and the type of
exposure (cadmium salt vs. cadmium fume and cadmium oxide).

EPA's RfD/RfC and CRAVE
workgroups were discontinued in May, 1995. Chemical substance reviews
that were not completed by September 1995 were taken out of IRIS review.
The IRIS Pilot Program replaced the workgroup functions beginning
in September, 1995.

04/01/1997

III., IV., V.

Drinking Water Health
Advisories, EPA Regulatory Actions, and Supplementary Data were removed
from IRIS on or before April 1997. IRIS users were directed to the
appropriate EPA Program Offices for this information.